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Combination Chemo-Rituximab Therapy Raises CLL Response Rates

Combination Chemo-Rituximab Therapy Raises CLL Response Rates

January 01, 2001

SAN FRANCISCOA regimen combining the monoclonal
antibody rituximab (Rituxan) with fludarabine (Fludara) and cyclophosphamide
may become the standard treatment for patients with chronic lymphocytic
leukemia (CLL). That projection is based on preliminary findings from a phase
II trial of 56 previously untreated patients with advanced CLL presented at the
American Society of Hematology annual meeting.

Complete remission rates with chlorambucil, the traditional
therapy for CLL, have been under 5%, said Michael J. Keating, MD, professor of
medicine, M.D. Anderson Cancer Center.

While fludarabine (introduced in the mid-1980s) brought the
complete response rate up to 30%, that advance did not translate into long-term
survival. "No one was cured of disease, and we needed to get above 50%
complete responses before there would be any prospect of patients with cancer
being cured," Dr. Keating said.

When research showed that fludarabine inhibited an important
resistance mechanism for alkylating agents, it was combined with the most
"user-friendly" alkylating agent, cyclophosphamide, and the result
was that the FC combination produced complete response rates of 40% to 45%, Dr.
Keating said.

Initially, rituximab was overlooked in CLL, because the partial
response rate in the pivotal trial of lymphocytic lymphoma (the lymphoma
counterpart of CLL) was only 12%. Based on the insight that rituximab’s short
half-life might require higher doses, investigators increased
doses sixfold without side effects and achieved partial response rates of about
75%.

"That convinced us that rituximab would be active in
CLL," Dr. Keating told ONI in an interview. He said that the researchers
had a hunch that fludarabine would make cells more susceptible to
chemotherapy, and that, plus some evidence that fludarabine would decrease
resistance proteins to rituximab, led to the current trial with the three-drug
(FCR) regimen.

The study included 68 patients with previously untreated
progressive or advanced CLL given FC (fludarabine 25 mg/m2, cyclophosphamide 250
mg/m2) daily for 3 days for 6 courses every 4 weeks
plus rituximab 375 mg/m2 on day 1 of course 1 and 500
mg/m2 on day 1 of courses
2 to 6.

In the ongoing trial, for patients completing 3 courses (n =
21), complete response is 14% and nodal partial response is 29%. For those
completing 6 courses
(n = 35), complete response is 57% and nodal partial response is 20% (see
Table). The overall response rate for the latter group is 94%.

"The initial data from this study suggest that the
addition of rituximab to fludarabine and cyclophosphamide leads to a complete
response rate that is clinically significantly higher than we have been able to
achieve with chemotherapy alone," Dr. Keating said.

He noted also that "in 71% of patients, we are currently
unable to find any CLL cells using the PCR [polymerase chain reaction]
techniquewhich can identify one cell in half a million."

The addition of rituximab to FC did not appear to cause a
clinically significant increase in adverse events, compared with those seen
with FC alone. The most commonly reported adverse event, neutropenia, led to an
FC dose reduction in 21% of patients.

During the first rituximab infusion, 61% of patients
experienced grade 1-2 and 14% experienced grade 3-4 toxicities.
Infusion-related events were uncommon in subsequent courses of rituximab. Tumor
lysis was noted in five patients before allopurinol prophylaxis was initiated.
After six courses, all responders except two partial responders had less than
5% CD5 and CD19 coexpressing lymphocytes in the marrow (median, 0.8%).

"With this protocol we have improved our complete response
rate, we haven’t increased toxicity, and we have the best quality remissions
that have been reported in CLLapart from transplantationwhich is clearly
a risky procedure to go through," Dr. Keating said. He stated furthermore
that with 90 patients currently enrolled in the trial, response rates remain
consistent "across the board."

"So this is virtually becoming our new standard of
treatment," Dr. Keating said, noting that the new task is to build on the
FCR success.

Next year, trials of antisense will be launched among patients
with bcl-2, an immortalizing protein that in CLL is almost always upregulated
dramatically. Antisense will be given prior to the FCR combination, Dr. Keating
said, to see if "we can shut down the bcl-2 protein" and make cells
more susceptible to chemotherapy.

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